The Inhabited Body
Companion Primer

Primer Chapter 1: The Living World — Life's Major Domains

This chapter is part of the companion primer to The Inhabited Body. It introduces the broadest categories of life on Earth, explains where viruses and other non-cellular entities fit, and provides the conceptual map that later chapters — both in this primer and in the main book — will build upon.

What Does It Mean to Be Alive?

Before we can talk about the microbes that share your body, we need to agree on what "alive" means. This turns out to be surprisingly difficult. Biologists have argued about it for centuries, and the argument is not settled.

Most working definitions of life include a short list of properties. A living thing takes in energy from its environment and uses it to maintain itself — a process called metabolism. It grows. It reproduces, making copies of itself that are similar but not always identical. It responds to its surroundings. And — critically — it carries hereditary information, a set of instructions that can be passed from one generation to the next and that can change over time, allowing populations to evolve.

These criteria work well for most of the organisms you are likely to think of. A dog is alive. A fern is alive. The bacterium swimming through your gut right now is alive. Each of these takes in energy, grows, reproduces, and carries a genome — a complete set of genetic instructions encoded in DNA.

But what about a virus? A virus carries genetic information. It evolves, sometimes with breathtaking speed. Yet it cannot reproduce on its own. It has no metabolism. Outside of a host cell, a virus is essentially an inert particle — a set of instructions wrapped in a protein coat, waiting. It does nothing until it encounters a cell it can hijack. Is it alive?

The honest answer is that there is no consensus. Some biologists treat viruses as living. Others treat them as biological entities that are not, strictly speaking, alive but are undeniably part of the living world — much as a computer virus is not a living thing but is certainly a participant in the digital ecosystem. For the purposes of this book, we will take the pragmatic view: viruses matter enormously to human biology and to the microbiome, regardless of whether we grant them the label "alive." We will meet them properly in Primer Chapter 5.

For now, let us focus on the organisms that everyone agrees are living — the cellular life forms — and ask a different question: how do we organise them?

Two Kingdoms, Five Kingdoms, Three Domains

For most of recorded history, people divided living things into two groups: animals and plants. It was an intuitive split. Animals moved; plants did not. Animals ate other organisms; plants drew sustenance from soil and sunlight. Aristotle used this framework. Linnaeus, the father of modern taxonomy, formalised it in the eighteenth century. For everyday purposes, it worked.

It did not work for microbes.

When Antonie van Leeuwenhoek peered through his handmade microscopes in the 1670s and saw what he called animalcules — tiny organisms teeming in pond water, in dental scrapings, in rainwater — the two-kingdom system immediately began to creak. Were these creatures animals? They moved, some of them, but they did not eat in any recognisable way. Were they plants? They had no leaves, no roots, no flowers. They were something else, and for the next three centuries, biologists struggled to fit them into a classification scheme that had not been designed for them.

By the mid-twentieth century, the prevailing view was that life could be divided into five kingdoms: Animals, Plants, Fungi, Protists (a grab-bag of single-celled organisms with complex cells), and Monera (bacteria and their relatives — single-celled organisms with simpler cells). This was better, but it still had problems. The kingdom Monera, in particular, lumped together organisms that looked similar under a microscope but turned out, at the molecular level, to be as different from each other as either was from you.

The revolution came from an unlikely source: a physicist-turned-microbiologist named Carl Woese, working at the University of Illinois. In the late 1970s, Woese had the idea of comparing organisms not by their physical appearance — which can be misleading, especially among microbes — but by the sequence of a particular molecule found in every living cell: ribosomal RNA, or rRNA. This molecule is part of the cellular machinery that translates genetic instructions into proteins. Because it performs the same essential job in every organism on Earth, it changes only slowly over evolutionary time. By comparing the sequence of rRNA between different species, Woese reasoned, you could build a family tree of all life — one based not on what organisms looked like, but on how they were actually related [woese1977].

What he found upended biology.

The organisms that had been lumped together as "bacteria" actually fell into two groups that were profoundly different from each other — as different, at the molecular level, as either was from animals or plants. One group was the true bacteria, which Woese called the Bacteria (or Eubacteria). The other was a previously unrecognised lineage that he called the Archaea — from the Greek for "ancient things" — because some of the first species discovered lived in extreme environments reminiscent of early Earth: boiling hot springs, highly acidic pools, oxygen-free muds.

In 1990, Woese, Otto Kandler, and Mark Wheelis formally proposed reorganising all of life into three great domains: Bacteria, Archaea, and Eukarya [woese1990]. The domains sat above kingdoms in the hierarchy of classification — a higher, more fundamental level of organisation. Animals, plants, fungi, and protists were all Eukarya. Every bacterium you had ever heard of belonged to Bacteria. And the Archaea were something else entirely — a third form of cellular life, hiding in plain sight.

The proposal was not warmly received. Woese was called a crank. One prominent biologist publicly dismissed the three-domain system as unnecessary. But the data accumulated, and by the mid-1990s, the three-domain framework had become the standard way that biologists understood the deepest divisions of life. Today, it remains the most widely used classification at this level, though as we shall see, even it has been challenged by newer discoveries.

Think of the three domains as three great continents on the map of life. Everything alive on Earth — every organism that metabolises, reproduces, and carries genetic information in the form of DNA — belongs to one of these three groups. The differences between them are not superficial. They go down to the very chemistry of their cells.

Domain 1: Bacteria — The Familiar Strangers

When most people hear the word "microbe," they think of bacteria. This is understandable. Bacteria are the microorganisms we encounter most often in daily life and in the news — from the Escherichia coli in our gut to the Streptococcus behind a sore throat to the Lactobacillus in a pot of yoghurt.

Bacteria are single-celled organisms. Each cell is small — typically between 0.5 and 5 micrometres in length, which means you could line up roughly a thousand of them across the head of a pin. They have no nucleus — no membrane-bound compartment to house their DNA. Instead, their genetic material floats freely within the cell in a concentrated region called the nucleoid. This is one of the defining features of what biologists call a prokaryotic cell (from the Greek pro, "before," and karyon, "kernel" or "nut" — a cell without a true kernel).

Despite their small size and apparent simplicity, bacteria are extraordinarily diverse. They come in several characteristic shapes — spheres (cocci), rods (bacilli), spirals (spirilla), and comma-shaped curves (vibrios) — but the real diversity lies in their metabolism. Some bacteria eat sugar. Some eat iron. Some eat rock. Some harvest energy from sunlight. Some thrive in boiling water; others flourish in Antarctic ice. Some require oxygen; others are killed by it. The metabolic versatility of bacteria is, without exaggeration, unmatched by any other domain of life.

How many bacterial species exist on Earth? This is a question with no settled answer. Estimates vary wildly depending on how you define a "species" (a surprisingly contentious issue among microbiologists) and how you count. A major census published in 2019 by Louca and colleagues analysed over 1.7 billion genetic sequences and estimated that there are between 0.8 and 1.6 million bacterial and archaeal species globally — of which roughly 690,000 distinct types were detected [louca2019]. Other analyses, using different mathematical models, have proposed numbers as high as one trillion species [locey2016]. The truth is that we do not know. What we do know is that only a tiny fraction of microbial species — perhaps 15,000 bacteria and a few hundred archaea — have been formally named and described in laboratory cultures.

For the purposes of this book, the important point is this: when we talk about the human microbiome, most of the organisms we are discussing are bacteria. They dominate the gut, the skin, the mouth, and most other body sites by both numbers and diversity. Understanding what bacteria are, how they live, and how they differ from other organisms is essential groundwork for everything that follows.

Domain 2: Archaea — The Hidden Third

If bacteria are the familiar strangers, archaea are the strangers you have never met — even though they have been living inside you all along.

Archaea look like bacteria. Under a microscope, you often cannot tell them apart. They are single-celled, prokaryotic (no nucleus), roughly the same size, and come in similar shapes. For decades, they were classified as bacteria. It took Woese's molecular revolution to reveal that beneath the surface, archaea are profoundly different.

The differences are chemical. Bacterial cell membranes are made of fatty acids linked to a glycerol backbone by a type of chemical bond called an ester linkage — the same basic membrane chemistry that your own cells use. Archaeal membranes are different: they use branched hydrocarbon chains joined to glycerol by ether linkages, a more stable arrangement that may help explain why many archaea can tolerate extreme conditions. Bacterial cell walls typically contain a molecule called peptidoglycan — a mesh-like polymer that gives the cell structural rigidity. Archaea lack peptidoglycan entirely. Their walls are built from different materials, including a variant sometimes called pseudopeptidoglycan, but the chemistry is distinct.

These are not trivial differences. They are roughly equivalent to discovering that two buildings that look identical from the outside are constructed from entirely different materials — one from brick and mortar, the other from interlocking carbon fibre. The external appearance is similar, but the engineering is fundamentally different.

The early archaea discovered by researchers tended to live in extreme environments — volcanic hot springs, ultra-salty lakes, the oxygen-free depths of swamp mud — which gave rise to the popular image of archaea as "extremophiles," organisms that thrive where nothing else can. This reputation, while not entirely wrong, is misleading. As molecular detection tools improved, researchers found archaea almost everywhere: in soil, in ocean water, in the guts of cattle, and — of direct relevance to this book — in the human body.

In the human microbiome, archaea are a minority but a consistent presence. The most commonly detected human-associated archaeon is Methanobrevibacter smithii, a methane-producing organism (a methanogen) found in the colon of most adults. M. smithii does not eat food directly. Instead, it consumes the waste products of bacterial fermentation — particularly hydrogen and carbon dioxide — and converts them to methane. In doing so, it removes hydrogen from the environment, which actually helps the bacteria around it ferment more efficiently. It is a partnership: the bacteria feed the archaea, and the archaea, by removing a waste product, help the bacteria work better. We will encounter this kind of metabolic cooperation repeatedly throughout the main book.

Perhaps the most profound insight from Woese's work — one that is still being refined today — is that archaea appear to be more closely related to us than to bacteria. The molecular machinery that archaea use to read their DNA and build proteins shares key features with the equivalent machinery in human cells. Some researchers now argue that eukaryotes — your domain, the domain of all complex life — actually evolved from within the archaea, making the archaea not merely our distant cousins but, in a sense, our ancestors [spang2015]. If this view is correct, the three-domain tree of life is really a two-domain tree, with Eukarya as a branch of Archaea. The debate is ongoing, but the direction of the evidence is clear: archaea are far more important to the story of life — including human life — than their obscurity in popular science would suggest.

Domain 3: Eukarya — The Complex Ones

The third domain is the one you belong to. Eukarya — from the Greek eu, "true," and karyon, "kernel" — encompasses every organism whose cells contain a true nucleus: a membrane-bound compartment that houses the DNA. This includes all animals, all plants, all fungi, and a vast assortment of single-celled organisms collectively (and somewhat unsatisfactorily) known as protists.

Eukaryotic cells are, as a rule, much larger and more complex than prokaryotic cells. A typical human cell is roughly 10 to 30 micrometres across — ten to sixty times the diameter of a typical bacterium, and perhaps a thousand times its volume. Inside, eukaryotic cells are divided into specialised compartments called organelles, each surrounded by its own membrane. The nucleus holds the DNA. The mitochondria — often called the "powerhouses of the cell" — generate most of the cell's energy. Plant cells have chloroplasts, which capture sunlight. There are internal transport systems, waste-processing centres, protein-packaging facilities. A eukaryotic cell is, by comparison to a bacterium, a small city.

How did this complexity arise? The leading explanation — now supported by overwhelming evidence — is endosymbiosis: the idea that certain key organelles in eukaryotic cells were once free-living prokaryotes that were engulfed by a larger cell and, over billions of years, became permanently integrated. Mitochondria are descended from ancient bacteria — almost certainly from a group related to modern Alphaproteobacteria. Chloroplasts are descended from ancient cyanobacteria, the photosynthetic bacteria that first oxygenated Earth's atmosphere. The host cell that engulfed them was, based on current evidence, most likely an archaeon or something very close to one.

This means that every cell in your body is, in a sense, a partnership. Your mitochondria still carry their own small genome — a remnant of their bacterial past. They still divide independently within the cell, on their own schedule. You are, at the cellular level, a collaboration between domains of life that diverged billions of years ago.

For the microbiome story, the relevant eukaryotes are primarily the fungi and the protists. Fungi — including yeasts, moulds, and mushrooms — are a kingdom of their own within Eukarya, and they are significant members of the human microbiome, particularly on the skin and in the gut. We will give them their own primer chapter (Primer Chapter 4). Protists — organisms like the Blastocystis species found in the gut of many healthy people — are rarer in the human microbiome but not absent, and their role is only beginning to be explored.

The Outliers: Viruses, Prions, and Other Entities

The three-domain system organises all cellular life. But the biological world contains entities that do not fit neatly into any domain because they are not cells at all.

Viruses

Viruses are the most numerous biological entities on Earth. Their estimated global count — roughly 10³¹ individual viral particles, or virions — exceeds the number of all cellular organisms combined. Yet they are not included in the three-domain tree because they lack the defining features of cellular life: they have no metabolism, no ribosomes, no capacity to grow or reproduce independently.

A virus is, at its simplest, a piece of genetic material — either DNA or RNA, but typically not both — wrapped in a protein shell called a capsid. Some viruses have an additional outer layer, an envelope, made of lipids stolen from the host cell. That is it. No cytoplasm, no membranes of their own, no energy-generating machinery. A virus reproduces by injecting its genetic material into a host cell and commandeering that cell's machinery to make copies of itself.

Viruses infect every domain of life. Some infect animals (influenza, SARS-CoV-2). Some infect plants (tobacco mosaic virus). Some infect bacteria — and these bacteria-infecting viruses, called bacteriophages (or simply phages), are of enormous importance to the microbiome. Phages are, by some estimates, the most abundant biological entities in the human gut. They shape bacterial communities by killing some species and sparing others, and they shuttle genes between bacteria in ways that can change what those bacteria do. We will devote considerable attention to phages in the main book (Chapters 16–18).

Proviruses and Prophages

Not all viruses immediately destroy their host. Some integrate their genetic material into the host's genome and stay there — quietly, sometimes for generations. When a virus does this to a bacterium, the integrated viral DNA is called a prophage, and the virus is said to be in its lysogenic cycle. The bacterium goes about its business, replicating the prophage DNA along with its own every time it divides. Under certain conditions — stress, DNA damage, changes in the environment — the prophage can reactivate, excise itself from the bacterial genome, and resume making new viral particles, typically destroying the host cell in the process.

When a virus integrates into the genome of a more complex organism — including a human — it can become an endogenous virus. The human genome contains thousands of fragments of ancient retroviruses, called human endogenous retroviruses (HERVs), that inserted themselves into our ancestors' DNA millions of years ago. Most are now broken and inert, but a few have been co-opted for essential functions. The protein syncytin, for instance — critical for the formation of the human placenta — is derived from an ancient retroviral envelope gene. We are, quite literally, built with viral spare parts. This story is told in detail in Chapter 2 of the main book.

Prions

At the far edge of biology sit prions — infectious agents that contain no genetic material at all. A prion is a misfolded protein: a normal cellular protein (called PrP) that has adopted an abnormal three-dimensional shape. The misfolded version can induce normally folded copies of the same protein to refold into the abnormal shape, creating a chain reaction that spreads through brain tissue. Prion diseases — including Creutzfeldt-Jakob disease in humans, BSE ("mad cow disease") in cattle, and scrapie in sheep — are invariably fatal and currently untreatable.

Prions are not part of the microbiome story, but they are worth mentioning here because they illustrate how broad the category of "biological entity" truly is. Life — or at least biological agency — does not require a cell, does not require a genome, and does not require metabolism. It requires only the ability to propagate information. A prion does exactly that, using protein shape rather than DNA as its information carrier.

Viroids and Obelisks

Finally, there are entities even simpler than viruses. Viroids are small, circular RNA molecules — no protein coat, no capsid, just naked RNA — that can infect plant cells and cause disease. They were discovered in 1971 and remain the smallest known infectious agents.

In 2024, a team led by Ivan Zheludev reported the discovery of a new class of viroid-like RNA elements in the human gut, which they named obelisks [zheludev2024]. These are tiny circular RNA molecules, found within bacteria in the gut microbiome, that appear to encode a single protein. They are not viruses, not viroids in the classical sense, and not part of any known category of biological entity. They are something new — a reminder that the catalogue of life's forms is still far from complete.

The Map of Life: Putting It All Together

Let us step back and survey the landscape. All cellular life on Earth belongs to one of three domains:

Beyond the cellular domains, the biological world includes:

This map is not complete — no map of life ever is — but it gives us the coordinates we need. In the chapters that follow, we will zoom in on each of these groups, examine their biology in more detail, and begin to understand why they matter to the story of human health.

Where This Matters in The Inhabited Body

Chapter References

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